Abstract
BACKGROUND: Remnant Cholesterol (RC) has emerged as a significant risk factor for cardiovascular disease. However, the factors influencing RC levels remain incompletely understood. This research investigates smoking-a major modifiable risk factor-to elucidate its impact on RC levels and examine the mediating role of inflammation in this relationship. METHODS: Using NHANES data from 1999 to 2018, this study analyzed the association between serum cotinine levels (a biomarker of smoking intensity) and RC in 8,829 participants aged 20 years and older. Through complex sampling design and adjustment for multiple covariables, we examined both linear and nonlinear relationships using linear regression models, restricted cubic splines (RCS), and subgroup analyses. Additionally, mediation analyses evaluated the role of inflammatory markers-neutrophils (NEU), monocytes (MON), lymphocytes (LYM), and platelets (PLT)-in this association. RESULTS: The high cotinine exposure group demonstrated significantly elevated RC levels (β = 2.256, 95% CI: 1.401-3.112, p < 0.001) compared to the no/minimal exposure group. This positive association was particularly pronounced in females (p for interaction < 0.05). Restricted cubic spline analysis demonstrated a nonlinear, N-shaped relationship (p for nonlinearity < 0.05), with RC levels reaching their peak at cotinine concentrations of approximately 172 ng/mL. In the mediation analysis, inflammatory markers showed significant mediating effects: NEU (28%), LYM (14.1%), PLT (9.5%), and MON (6.9%) of the total effect. CONCLUSION: A significant positive association exists between cotinine and RC levels, moderated by sex. Inflammatory markers, particularly NEU, partially mediate this association.